The goal of this proposal is to further my development as a clinical investigator and support the training of future physician-scientists. With the support of this grant, I will continue to focus my efforts on designing and implementing individualized mentoring plans in the context of improving our understanding of bone biology and osteoporosis therapy. The mentoring plans, while targeted to each trainee's experience level, consist of didactic training, participation and integration into the Endocrine Unit's rich research environment, and the supervised completion of a novel and impactful project. The outstanding training environment of the Massachusetts General Hospital Endocrine Unit and the significant support of the Endocrine Unit leadership further strengthen this application. The clinical investigation techniques and procedures described in this proposal are novel, clinically relevant, and provide current and future trainees with opportunities to gain experience in all aspects of clinical trial implementation. Furthermore, our studies utilize the most innovative and exciting methods available in bone-related human investigation. Specifically, our experience with high-resolution peripheral quantitative computed tomography allows us to move beyond standard measurements of bone mineral density to investigate the effects of interventions on bone geometry, structure and microarchitecture while our utilization of finite element analysis allows for the longitudinal evaluation of estimated bone strength at the most clinically relevant sites. Finally, our capacity to measure bone material properties in vivo using the recently-introduced microindentation technique allows for the direct determination of cortical bone material strength. This award will permit me to substantially decrease my clinical and administrative duties and expand my mentoring responsibilities. Moreover, it will allow me to continue to direct clinical studies with the potential to significantly improve the management of patients with severe osteoporosis.